Abstract
Renal hypouricemia (RHUC) is caused by an inherited defect in the main reabsorption system of uric acid, SLC22A12 (URAT1) and SLC2A9 (GLUT9). RHUC is characterized by a decreased serum uric acid concentration and an increase in its excreted fraction. Patients suffer from hypouricemia, hyperuricosuria, urolithiasis, and even acute kidney injury. We report clinical, biochemical, and genetic findings in a cohort recruited from the Košice region of Slovakia consisting of 27 subjects with hypouricemia and relatives from 11 families, 10 of whom were of Roma ethnicity. We amplified, directly sequenced, and analyzed all coding regions and exon–intron boundaries of the SLC22A12 and SLC2A9 genes. Sequence analysis identified dysfunctional variants c.1245_1253del and c.1400C>T in the SLC22A12 gene, but no other causal allelic variants were found. One heterozygote and one homozygote for c.1245_1253del, nine heterozygotes and one homozygote for c.1400C>T, and two compound heterozygotes for c.1400C>T and c.1245_1253del were found in a total of 14 subjects. Our result confirms the prevalence of dysfunctional URAT1 variants in Roma subjects based on analyses in Slovak, Czech, and Spanish cohorts, and for the first time in a Macedonian Roma cohort. Although RHUC1 is a rare inherited disease, the frequency of URAT1-associated variants indicates that this disease is underdiagnosed. Our findings illustrate that there are common dysfunctional URAT1 allelic variants in the general Roma population that should be routinely considered in clinical practice as part of the diagnosis of Roma patients with hypouricemia and hyperuricosuria exhibiting clinical signs such as urolithiasis, nephrolithiasis, and acute kidney injury.
Highlights
Hypouricemia, defined as a serum uric acid (UA) concentration < 120 μmol/L, is a rare laboratory finding with a prevalence of 0.21–0.53% that varies with age [1,2]
Renal hypouricemia (RHUC) is a rare heterogeneous inherited disease caused by a dysfunction of the primary renal urate transporters: URAT1
The disease presents with urolithiasis, nephrolithiasis, and, in some patients, acute kidney injury that often occurs after physical exertion [8]
Summary
Primary hypouricemia can result from decreased UA production by a blockade of the last step of purine degradation, e.g., hereditary xanthinuria, but is more commonly due to decreased renal tubular UA reabsorption, e.g., renal hypouricemia. Renal hypouricemia (RHUC) is a rare heterogeneous inherited disease caused by a dysfunction of the primary renal urate transporters: URAT1 (gene SLC22A12, OMIM #220150). GLUT9 (gene SLC2A9, OMIM #612076), resulting in impaired tubular transport of UA, insufficient reabsorption, and/or increased secretion by a mechanism of endothelial dysfunction [3,4,5,6,7]. The disease presents with urolithiasis, nephrolithiasis, and, in some patients, acute kidney injury that often occurs after physical exertion [8]. No treatment is available; allopurinol has been used to prevent the recurrence of acute kidney injury episodes [9]
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